Targeting B-cells mitigates autoimmune diabetes in NOD mice: what is plan B?

n this issue of Diabetes, Grey and colleagues (1) demonstrate that therapeutic B-cell depletion delays diabetes onset and reduces diabetes incidence in NOD mice. B-cell depletion in pre-diabetic NOD mice was accomplished using an extended regime of recombinant B-cell maturation antigen (BCMA)-Fc chimerized protein that targets B-lymphocyte stimulator (BLyS)/B-cell-activating factor of the tumor necrosis factor family (BAFF)-a cytokine critical for maintenance of the peripheral B-cell pool. This follows recent studies demonstrating significant effects of B-cell depletion on diabetes onset and severity (2-5); however, no other studies have reported profound and complete protection from hyperglycemia as observed here. Following B-cell depletion therapy during 9 -15 weeks of age, NOD mice remained diabetes free for 50 weeks of age, even after B-cell reconstitution. An increase in CD25 Foxp3 CD4 regulatory T-cells (Tregs) following B-cell depletion may mediate prolonged tolerance given that the CD25 monoclonal antibody (mAb) treatment neutralized the long-term therapeutic benefits of B-cell depletion (Fig. This mechanism may explain why B-cell-deficient NOD.MT mice do not develop hyperglycemia given that autoimmune diabetes was also precipitated in these mice by Treg depletion.